Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Bruno, Agostino; Amori, Laura; Costantino, Gabriele

doi:10.1002/minf.201000162

Cited by 8 publications

(10 citation statements)

References 46 publications

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“…Despite the range of activity allowed only a rough SAR, these results somehow confirmed the presence of a lipophilic pocket in the proximity of the enzyme active site where the pyrazole substituent can locate, as previously noticed by us 27 , 36 , 37 . In addition, the activity shown by compounds 4e and 5f demonstrated that the size of the molecule may have some influence on the binding to the enzyme pocket.…”

Section: Resultssupporting

confidence: 84%

Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Magalhães

Franko

Annunziato

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Several bacteria rely on the reductive sulphur assimilation pathway, absent in mammals, to synthesise cysteine. Reduction of virulence and decrease in antibiotic resistance have already been associated with mutations on the genes that codify cysteine biosynthetic enzymes. Therefore, inhibition of cysteine biosynthesis has emerged as a promising strategy to find new potential agents for the treatment of bacterial infection. Following our previous efforts to explore OASS inhibition and to expand and diversify our library, a scaffold hopping approach was carried out, with the aim of identifying a novel fragment for further development. This novel chemical tool, endowed with favourable pharmacological characteristics, was successfully developed, and a preliminary Structure–Activity Relationship investigation was carried out.

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Section: Resultssupporting

confidence: 84%

Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Magalhães

Franko

Annunziato

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In fact, if a virtual screening is carried using the open conformation, less specific compounds might be identified, whereas if the screening is carried out using the closed conformation, the reduced space may lead to the identification of ligands with reduced size and affinity. In an effort to overcome these limitations and to include SerR conformational flexibility in virtual screening investigations, targeted molecular dynamics of SerR was combined with conformational sampling and docking studies . Results suggest that a virtual screenings of SerR carried out sampling a defined number of protein conformations along the open-to-closed state pathway might lead to the identification of selective and high affinity enzyme inhibibitors.…”

Section: Amino Acid Racemases As Drug Targetsmentioning

confidence: 99%

Drug Discovery Targeting Amino Acid Racemases

Conti¹,

Tamborini²,

Pinto³

et al. 2011

Chem. Rev.

112

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Amino acids are among the most important molecules in nature since they play central roles both as building blocks of proteins and as intermediates in metabolism. The amino acid sequence dictates protein folding, the native three dimensional structure, and protein stability. Furthermore, the peculiar chemical properties of the amino acids forming the active site and their interplay determine protein function and regulation. All amino acids found in proteins, except glycine, possess a stereogenic center at the a-carbon atom. Millions of years of evolution have resulted in the virtually complete homochirality of such a stereogenic center, i.e. the L-enantiomer, in mammals. 1 This selection of the L-amino acids by nature is generally considered to be a result of chance. 2 Since the cornerstone of the protein-ligand recognition is the multi-point attachment theory, it turns out that the configuration of the a-carbon atom of amino acids strongly affects the protein-ligand interaction. Nevertheless, during the last half of the twentieth century, various studies evidenced the presence of Damino acids in some plants and bacteria. 3,4 These compounds were either found in a free state or in peptides and proteins. Most bacteria produce significant amounts of D-alanine (D-Ala) and D-glutamate (D-Glu), which are incorporated into peptidoglycan. 5 Peptidoglycan is a strong and elastic polymer of the bacterial wall, which is capable to counteract the osmotic pressure of the cell, maintaining cell shape and anchoring components of the cell envelope. 6 The number of D-amino acids present in the structure of peptidoglycan seems to constitute a measure of protection against peptidase and protease attacks. So far, no peptidase capable of hydrolyzing a peptide bond characterized by the sequence D-D or D-L amino acids has been isolated in mammals. In addition, several antibiotics produced by prokaryotes (e.g. bacitracin, actinomycin D) contain D-amino acids (Figure 1). It has been recently demonstrated that bacteria synthesize a pool of different D-amino acids, including D-methionine (D-Met) and D-leucine (D-Leu) in Vibrio cholerae and D-tyrosine (D-Tyr) and D-phenylalanine (D-Phe) in Bacillus subtilis. By selectively incorporating them in the peptidoglycan cell wall, bacteria cope to different environmental stresses. 7

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“…Nevertheless, it can be expected that the individual enzyme conformations captured by X‐ray crystallography are not sufficient to display all the features needed for a proper interaction with the substrate or with the inhibitors. In this context, MD simulations have already proven to be useful tools to catch the structural details of the inhibition mechanism for compounds targeting β‐family PLP‐dependent enzymes 20…”

Section: Introductionmentioning

confidence: 99%

Computational Insights into the Mechanism of Inhibition of OASS‐A by a Small Molecule Inhibitor

Bruno

Amori

Costantino

2013

Molecular Informatics

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O-Acetylserine sulfhydrylase (isoform A, OASS-A) is a PLP-dependent enzyme involved in the last step of cysteine biosynthesis in many pathogens. Many microorganisms use cysteine as the main building block for sulfur-containing antioxidants, and cysteine depletion in several pathogens resulted in a reduced antibiotic resistance, thus leading to the identification of OASS as novel suitable molecular targets to overcome antimicrobial resistances. The precise molecular mechanism of OASS-A inhibition by small peptides or by small molecule inhibitors is still unclear. To shed more lights on the structural basis underlying the inhibition mechanism for OASS, we engaged ourselves in studying the dynamic properties of this enzyme. In this paper, we describe a computational study involving unbiased MD simulations of OASS-A from Haemophilus influenzae (HiOASS) in its inhibitor free, PLP-bound form, and in complex with a pentapeptide inhibitor and with UPAR40, a small molecule which we have recently reported as a potent OASS-A inhibitors. We proposed that UPAR40 inhibits HiOASS-A through the stabilization of a closed conformation. Moreover, preliminary docking studies and sequence analysis allow us to speculate about the non-specificity of UPAR40 toward a particular OASS enzyme species or isoforms.

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Addressing the Conformational Flexibility of Serine Racemase by Combining Targeted Molecular Dynamics, Conformational Sampling and Docking Studies

Cited by 8 publications

References 46 publications

Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Drug Discovery Targeting Amino Acid Racemases

Computational Insights into the Mechanism of Inhibition of OASS‐A by a Small Molecule Inhibitor

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